Inhibition of the NLRP3 inflammasome prevents ovarian aging

Inflammation is a hallmark of aging and is negatively affecting female fertility. In this study, we evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in WT mice during reproductive aging. High expression of NLRP3, caspase-1, and IL-1β was also observed in granulosa cells from patients with ovarian insufficiency. Ablation of NLRP3 improved the survival and pregnancy rates and increased anti-Müllerian hormone levels and autophagy rates in ovaries. Deficiency of NLRP3 also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of Nlrp3−/− mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.

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Inhibition of the NLRP3 inflammasome prevents ovarian aging

10.1101/2020.04.26.062646 ◽

2020 ◽

Author(s):

José M. Navarro-Pando ◽

Elísabet Alcocer-Gómez ◽

Beatriz Castejón-Vega ◽

Jordi Muntané ◽

Pedro Bullon ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Ovarian Tissue ◽

Female Fertility ◽

Reproductive Aging ◽

Ovarian Insufficiency ◽

Ovarian Aging ◽

Age Dependent ◽

Estradiol Levels ◽

Hormonal Levels

Inflammation is a hallmark of many processes during aging and reproductive physiology, negatively affecting female fertility. The goal of this study was to evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in female WT mice during reproductive aging. High expression of NLRP3, caspase 1 and IL-1β was also observed in granulosa cells from patients with primary ovarian insufficiency. Ablation of the NLRP3 inflammasome improved the survival and pregnancy rates in mice, increased hormonal levels of AMH, a biochemical marker of ovarian reserve, and autophagy rates in ovarian tissue. Deficiency of the NLRP3 inflammasome also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of Nlrp3−/− mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.

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Mitochondrial Dysfunction and Ovarian Aging

Endocrinology ◽

10.1210/endocr/bqaa001 ◽

2020 ◽

Vol 161 (2) ◽

Cited By ~ 4

Author(s):

Işıl Kasapoğlu ◽

Emre Seli

Keyword(s):

Mitochondrial Dysfunction ◽

Ovarian Reserve ◽

Reproductive Aging ◽

Ovarian Dysfunction ◽

Ongoing Research ◽

Ovarian Aging ◽

Age Related ◽

Age Related Changes

Abstract As women delay childbearing because of demographic and socioeconomic trends, reproductive aging and ensuing ovarian dysfunction become increasingly more prevalent causes of infertility. Age-related decline in fertility is characterized by both quantitative and qualitative deterioration of the ovarian reserve. Importantly, disorders of aging are frequently associated with mitochondrial dysfunction, as are impaired oogenesis and embryogenesis. Ongoing research explores the role of mitochondrial dysfunction in ovarian aging, and potential ways to exploit mitochondrial mechanisms to slow down or reverse age-related changes in female gonads.

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Emerging Role of the NLRP3 Inflammasome and Interleukin-1β in Neonates

Neonatology ◽

10.1159/000507584 ◽

2020 ◽

pp. 1-10

Author(s):

Murwan Omer ◽

Ashanty Maggvie Melo ◽

Lynne Kelly ◽

Emma Jane Mac Dermott ◽

Timothy Ronan Leahy ◽

...

Keyword(s):

Cerebral Palsy ◽

Nlrp3 Inflammasome ◽

Therapeutic Target ◽

Inflammasome Activation ◽

Neonatal Brain ◽

Persistent Inflammation ◽

Attractive Therapeutic Target ◽

Clinical Models ◽

Novel Therapeutic

Infection and persistent inflammation have a prominent role in the pathogenesis of brain injury and cerebral palsy, as well as other conditions associated with prematurity such as bronchopulmonary dysplasia. The NLRP3 inflammasome-interleukin (IL)-1β pathway has been extensively studied in adults and pre-clinical models, improving our understanding of innate immunity and offering an attractive therapeutic target that is already contributing to clinical management in many auto-inflammatory disorders. IL-1 blockade has transformed the course and outcome of conditions such as chronic infantile neurological, cutaneous, articular (CINCA/NOMID) syndrome. Inflammasome activation and upregulation has recently been implicated in neonatal brain and lung inflammatory disease and may be a novel therapeutic target.

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The m6A mRNA demethylase FTO in granulosa cells retards FOS-dependent ovarian aging

Cell Death and Disease ◽

10.1038/s41419-021-04016-9 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Zhong-xin Jiang ◽

Yi-ning Wang ◽

Zi-yuan Li ◽

Zhi-hui Dai ◽

Yi He ◽

...

Keyword(s):

Granulosa Cells ◽

Therapeutic Target ◽

Rna Sequence ◽

Ovarian Aging ◽

Age Related ◽

Fos Expression

AbstractMultifunctional N6-methyladenosine (m6A) has been revealed to be an important epigenetic component in various physiological and pathological processes, but its role in female ovarian aging remains unclear. Thus, we demonstrated m6A demethylase FTO downregulation and the ensuing increased m6A in granulosa cells (GCs) of human aged ovaries, while FTO-knockdown GCs showed faster aging-related phenotypes mediated. Using the m6A-RNA-sequence technique (m6A-seq), increased m6A was found in the FOS-mRNA-3′UTR, which is suggested to be an erasing target of FTO that slows the degradation of FOS-mRNA to upregulate FOS expression in GCs, eventually resulting in GC-mediated ovarian aging. FTO acts as a senescence-retarding protein via m6A, and FOS knockdown significantly alleviates the aging of FTO-knockdown GCs. Altogether, the abovementioned results indicate that FTO in GCs retards FOS-dependent ovarian aging, which is a potential diagnostic and therapeutic target against ovarian aging and age-related reproductive diseases.

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Melatonin Represses Mitophagy to Protect Mouse Granulosa Cells from Oxidative Damage

Biomolecules ◽

10.3390/biom11070968 ◽

2021 ◽

Vol 11 (7) ◽

pp. 968

Author(s):

Yi Jiang ◽

Ming Shen ◽

Yuanyuan Chen ◽

Yinghui Wei ◽

Jingli Tao ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Kinase ◽

Circadian Rhythms ◽

Oxidative Damage ◽

Cell Viability ◽

Granulosa Cells ◽

Therapeutic Target ◽

Potential Therapeutic Target ◽

Protective Mechanisms

Various environmental stimuli, including oxidative stress, could lead to granulosa cell (GC) death through mitophagy. Recently, it was reported that melatonin (MEL) has a significant effect on GC survival during oxidative damage. Here, we found that MEL inhibited oxidative stress-induced mitophagy to promote GC survival. The loss of cell viability upon H2O2 exposure was significantly restored after MEL treatment. Concomitantly, MEL inhibited the activation of mitophagy during oxidative stress. Notably, blocking mitophagy repressed GC death caused by oxidative stress. However, MEL cannot further restore viability of cells treated with mitophagy inhibitor. Moreover, PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase, was inhibited by MEL during oxidative stress. As a result, the E3 ligase Parkin failed to translocate to mitochondria, leading to impaired mitochondria clearance. Using RNAi to knock down PINK1 expression, we further verified the role of the MEL-PINK1-Parkin (MPP) pathway in maintaining GC survival by suppressing mitophagy. Our findings not only clarify the protective mechanisms of MEL against oxidative damage in GCs, but also extend the understanding about how circadian rhythms might influence follicles development in the ovary. These findings reveal a new mechanism of melatonin in defense against oxidative damage to GCs by repressing mitophagy, which may be a potential therapeutic target for anovulatory disorders.

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Combining Bioinformatics and Experiments to Identify CREB1 as a Key Regulator in Senescent Granulosa Cells

Diagnostics ◽

10.3390/diagnostics10050295 ◽

2020 ◽

Vol 10 (5) ◽

pp. 295 ◽

Cited By ~ 2

Author(s):

Pei-Hsuan Lin ◽

Li-Te Lin ◽

Chia-Jung Li ◽

Pei-Gang Kao ◽

Hsiao-Wen Tsai ◽

...

Keyword(s):

Gene Expression ◽

Granulosa Cells ◽

Mitochondrial Dynamics ◽

Ros Production ◽

Oxygen Species ◽

Mitochondrial Reactive Oxygen Species ◽

Ovarian Aging ◽

Gene Expression Analyses ◽

Underlying Mechanisms

Aging of functional ovaries occurs many years before aging of other organs in the female body. In recent years, a greater number of women continue to postpone their pregnancies to later stages in their lives, raising concerns of the effect of ovarian aging. Mitochondria play an important role in the connection between the aging granulosa cells and oocytes. However, the underlying mechanisms of mitochondrial dysfunction in these cells remain poorly understood. Therefore, we evaluated the molecular mechanism of the aging granulosa cells, including aspects such as accumulation of mitochondrial reactive oxygen species, reduction of mtDNA, imbalance of mitochondrial dynamics, and diminished cell proliferation. Here, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of CREB1 gene expression in reproduction. Senescence hallmark enrichment and pathway analysis suggested that the downregulation of bioenergetic-related genes in CREB1. Gene expression analyses showed alterations in genes related to energy metabolism and ROS production in ovary tissue. We also demonstrate that the biogenesis of aging granulosa cells is subject to CREB1 binding to the PRKAA1 and PRKAA2 upstream promoters. In addition, cofactors that regulate biogenesis significantly increase the levels of SIRT1 and PPARGC1A mRNA in the aging granulosa cells. These findings demonstrate that CREB1 elevates an oxidative stress-induced senescence in granulosa cells by reducing the mitochondrial function.

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BRCA1, BRCA2 and primary ovarian insufficiency

E3S Web of Conferences ◽

10.1051/e3sconf/202016505009 ◽

2020 ◽

Vol 165 ◽

pp. 05009

Author(s):

Yinuo Zhang

Keyword(s):

Primary Ovarian Insufficiency ◽

Dna Breaks ◽

Brca1 And Brca2 ◽

Dsb Repair ◽

Ovarian Insufficiency ◽

Ovarian Aging ◽

Brca Genes ◽

Mutation Carriers ◽

Increased Risk

BRCA1 and BRCA2 genes belong to the family of ataxia-telangiectasia-mutated (ATM)-mediated DNA DSB repair genes that play a critical role in the DNA double-strand break (DSB) repair. Mutations in BRCA genes significantly increase the lifetime risk of breast, ovarian, fallopian tube and primary peritoneal cancers. In addition to the increased risk for multiple malignancies, recent literature suggest that mutations in BRCA genes could lead to decreased ovarian reserve and subsequent ovarian aging. In this review, we will focus on role of BRCA1 and BRCA2 in ovarian function, particularly ovarian aging and primary ovarian insufficiency. Serum AMH values are generally lower in BRCA1 mutation carriers but not in BRCA2 mutation carriers. BRCA2 carriers were more likely to have chemotherapy-induced amenorrhea DNA not stable, linking with ovarian aging. The mechanism by which BRCAs mutation in the pathogenesis of POI is the inpaired function of repairing DNA breaks. Future studies investigating the knockout models to elucidate the role of the BRCAs genes in ovarian development and oocyte maturation will be interesting.

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P–139 The role of hormones and LH receptor expression of granulosa cells collected from large and small follicles in natural/minimal stimulation cycle IVF

Human Reproduction ◽

10.1093/humrep/deab130.138 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

T Okubo ◽

H Teruaki ◽

O Noriyuki ◽

O Kenji ◽

S Tomoya

Keyword(s):

Mrna Expression ◽

Granulosa Cells ◽

Receptor Expression ◽

Mrna Levels ◽

Lh Receptor ◽

Small Follicle ◽

Estradiol Levels ◽

Natural Cycles ◽

Follicular Fluids

Abstract Study question Do different follicle sizes influence gonadotropins (LH, FSH) and sex steroid (estradiol) in follicular fluids and LH receptor expression (LHCGR) in cumulus oocyte complexes (COCs)? Summary answer It was found that differences in levels of FSH, estradiol values and LHCGR mRNA expression level in COCs between small and large follicles. What is known already The maturity rate in oocytes of small follicle is significantly lower compared to that of large follicles. Study design, size, duration After obtaining written consents from 78 infertile patients, we aspirated the large (>15 mm) and small (<5 mm) follicles, and collected follicular fluids at oocyte retrieval. Participants/materials, setting, methods We measured levels of LH, FSH and estradiol by enzyme immunoassay from large and small follicular fluids after oocytes retrievals. All collected oocytes were distinguished from large and small follicles, we confirmed the maturity of retrieved oocytes by the presence of first polar body. Then we extracted total RNA from granulosa cells and measured mRNA expression of LHCGR, encoding the human LH receptor, by quantitative real-time PCR. Each value was normalized to ACTB mRNA levels. Main results and the role of chance LH levels were nearly equal between small and large follicles (P = 0.8356). Whereas FSH and estradiol levels were significantly lower in small follicles (P < 0.0001). The expression levels of LHCGR mRNA were significantly lower in small follicles than in large follicles during natural cycles. The maturity rate in oocytes of small follicle was significantly lower compared to that of large follicles (96.0% vs. 21.7%, P < 0001). Limitations, reasons for caution The main limitation of the present study was collected by 42 natural cycles and 36 mild stimulation cycles with letrozole following low-dose clomiphene. Wider implications of the findings: In spite of almost the same LH levels between two groups, the reason why the significantly lower maturation rates of oocytes collected from small follicles is poor LHCGR mRNA expression due to insufficient granulosa cells glowth because of low FSH and estradiol levels. Trial registration number Not applicable

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